Biological rhythm disturbances have been described in patients with depression. Experimental manipulation of these rhythms by sleep deprivation, or phototherapy can produce marked changes in mood, suggesting that alterations in the circadian rhythms of patients with affective disorders play an important role in the pathophysiology of these disorders. As we have noted in our previous annual report Z01 MH 00450 10 CP, circadian oscillators cannot be measured directly. In our present study a more precise description of the intrinsic properties of the biological clocks in depression are obtained by observing patients and normal controls under constant conditions of diet, physical activity, wakefulness, and illumination. Thus far we have studied 12 patients and 7 age and sex-matched normal controls. Preliminary data from our study of neurotransmitter metabolites indicates that a previously described rhythm in the norepinephrine metabolite MHPG in the plasma is the result of external factors. Although no rhythm in MHPG was found, depressed patients had significantly lower plasma MHPG than controls and this difference could not be attributed to physical activity, diet or disrupted sleep. By contrast, a circadian variation in dopamine metabolite, HVA, was observed with peak values seen at night, which persists under constant conditions. No patient normal differences were noted in this variable. Already this design appears useful in discriminating between circadian variability arising from intrinsic versus extrinsic factors and the study of physiologic variables under constant conditions has implications beyond circadian research.